A number sign (#) is used with this entry because of evidence that hypotrichosis-6 (HYPT6) is caused by homozygous or compound heterozygous mutation in the gene encoding desmoglein-4 (DSG4; 607892) on chromosome 18q12.

For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see 605389.

Hypotrichosis-6 (HYPT6) is a localized autosomal recessive hypotrichosis characterized by fragile hairs that break easily, leaving short, sparse scalp hairs. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas. In some patients with congenital hypotrichosis, monilethrix-like hairs showing elliptical nodes have been observed (summary by Schaffer et al., 2006).

Genetic Heterogeneity of Autosomal Recessive Localized Hypotrichosis

LAH2 (HYPT7; 604379) is caused by mutation in the LIPH gene (607365) on chromosome 3q27, and LAH3 (HYPT8; 278150) is caused by mutation in the LPAR6 (P2RY5) gene (609239) on chromosome 13q14.12-q14.2.

See also hypotrichosis and recurrent skin vesicles (613102), which is caused by mutation in the DSC3 gene (600271).

Hanhart (1955) reported a sister and brother with hypotrichosis who were born of first-cousin Swiss parents. At 21 years of age, the proband had dark brown hair that was partly normal and partly made up of thin, rough hairs that were broken off at different lengths; microscopic examination showed the characteristic regular 'spindles' of monilethrix (see 158000). Keratosis follicularis was present on her occipital scalp and neck. Her axillary and pubic hair were also affected, and again only part of the hair was involved. She was also reported to be intellectually impaired. Her 37-year-old brother had similar hair with extensive balding, but 2 other sibs had normal hair, and the brother had 3 daughters with normal hair. Salamon and Schnyder (1962) later examined the parents and found no monilethrix-like hairs or keratosis follicularis; they also reported that the proband had a 3-year-old daughter with normal hair.

Kljuic et al. (2003) reported 2 consanguineous Pakistani pedigrees with autosomal recessive localized hypotrichosis and mutation in the DSG4 gene. Affected members displayed hypotrichosis restricted to the scalp, chest, arms, and legs. Facial hair, including eyebrows and beard, was less dense, and axillary hair, pubic hair, and eyelashes were spared. Overall, the patients' skin was normal except for patches of scalp where small papules were visible, likely a consequence of ingrown hairs. Histologic analysis of scalp skin revealed abnormal hair follicles and shafts, which were thin and atrophic and often appeared coiled up within the skin due to their inability to penetrate the epidermis. Another defect was a marked swelling of the precortical region, resulting in the formation of a bulbous 'bleb' within the base of the hair shaft.

Rafique et al. (2003) described multiple members of 3 consanguineous kindreds from different regions of Pakistan who had LAH. They had hair on the scalp at birth, which regrew sparsely after ritual shaving at 1 week of age. They were nearly devoid of normal eyebrows and eyelashes, but their axillary and pubic hair was normal. Affected males had normal beard hair, but no hair on their arms or legs. Rafiq et al. (2004) identified mutation in the DSG4 gene in affected members of these 3 families.

Shimomura et al. (2006) studied a Japanese girl with congenital hypotrichosis and mutation in the DSG4 gene. She had short, dry, brittle, and lusterless scalp hairs, most of them emerging from keratotic follicular papules and breaking easily. Her eyebrows were also sparse, whereas her eyelashes were spared; nails and teeth were normal. At 7 months of age, her hair shafts showed no abnormalities under light microscopy, but scanning electron microscopy (SEM) revealed that the thickness of the shaft varied in some parts, resulting in nodes of normal thickness and abnormally thin internodes without regular periodicity. Breaks in the hair shaft always occurred at internodes, which at higher magnification were seen to have longitudinal ridges. Distal portions of some hairs were tapered and kept their cuticular scales, whereas others showed roughly broken bundles of cortical fibers. At 2 years of age, the patient had long terminal hairs which looked normal even by SEM, but short broken hairs were also present which showed the same abnormalities as previously observed, features resembling those of moniliform hair seen in monilethrix.

Schaffer et al. (2006) described 3 sibs of Iraqi and Iranian Jewish descent with monilethrix-like congenital hypotrichosis and mutation in the DSG4 gene. The proband was a 2-year-old girl who was born with sparse, stubbly hair and a complete lack of eyebrows and eyelashes, who subsequently developed coarse, short, brittle hairs over most of the scalp, appearing as stubble and 'black dots' clinically. The hair growth was accompanied by numerous follicular papules on the scalp, associated with mild erythema, a variable degree of keratosis, and severe pruritus. She had no palmoplantar keratoderma or hypohidrosis, other skin lesions, or abnormalities of the teeth or nails. Her 4-month-old affected fraternal twin brothers were born with scattered, patchy areas of dark stubble on the scalp. Neither twin had eyebrow hairs; 1 had sparse eyelashes. All 3 sibs had crusting erosions of the scalp in the neonatal period that subsequently healed and did not recur. Light microscopy of hairs from the proband revealed an uneven, undulating diameter, and some areas appeared as separate elliptical nodal fragments with tapered ends. Many hairs displayed trichoschisis characterized by rounded, frayed ends, whereas other hairs showed bent shafts or longitudinal twisting suggestive of pili torti. Scalp biopsy of the proband at 18 months of age showed a normal density of terminal anagen hair follicles but with a markedly irregular structure, including 2 or 3 hair follicles converging in a single ostium. The formation of dilated 'blebs' was evident in the hair shafts of some follicles. There was an irregular boundary between the inner root sheath and the hair shaft, and the cortex of the shafts was distorted in appearance. Some hair shafts exhibited a jagged shape and fragmentation. The interfollicular epidermis was slightly hyperplastic with focal parakeratosis.

Zlotogorski et al. (2006) studied 12 Jewish families of Iraqi, Iranian, and Moroccan descent who had hypotrichosis and mutation in the DSG4 gene. All patients had early-onset generalized scalp alopecia within the first days of life, with a 'black dots' appearance. Follicular hyperkeratotic papules on the scalp, accompanied by erythema, scaling, dryness, and pruritus were also noted in infancy. Improvement in hair growth was documented towards the end of the second year of life, with patchy or widespread alopecia, especially of the posterior scalp. Hairs in general were short and brittle, but some reached a length of 10 to 20 cm. Two or 3 hair follicles infrequently converged in a single ostium. Eyebrows and eyelashes were sparse, with no body hair, decreased axillary hair, and sparing of pubic hair. Hyperkeratotic papules were most common on the lower posterior scalp and nape of neck, with a variable number of papules on the extensor surfaces of the upper arm and thigh and periumbilical area. Nails, teeth, and sweating were normal. The common hair abnormality was the elliptical node typical of monilethrix. Other occasionally seen hair abnormalities included pili torti, trichoschisis, trichorrhexis nodosa-like defects, and tapered hairs.

Wajid et al. (2007) examined 6 affected individuals from a large consanguineous Pakistani family with hypotrichosis of varying severity and mutation in the DSG4 gene. All affected children were born without hair. After ritual shaving at approximately 3 weeks of age, sparse and coarse hair growth occurred that was sometimes accompanied by itching, redness, and roughness of the scalp. Fragile hairs were present in all affected individuals. Comparison of the clinical findings in the 4 male patients revealed marked variability that was not age-dependent in terms of severity: 2 boys, ages 5 and 7 years, had a relatively mild phenotype, sparing the eyebrows and lashes; a 17-year-old boy had follicular hyperkeratosis, erythema, and scaling affecting the scalp, eyebrows, and eyelashes; and the most severely affected individual was almost completely without hair at 13 years of age. Hair shafts from affected males showed tapered broken ends in addition to monilethrix-like nodes. All affected individuals had normal teeth, nails, and sweating, and their skin was otherwise normal with no papular lesions on the limbs and no palmoplantar keratoderma. Despite the marked variation in severity, Wajid et al. (2007) stated that the clinical findings were most consistent with a diagnosis of localized autosomal recessive hypotrichosis.

Wang et al. (2015) reported a 2-year-old Chinese girl with monilethrix-like hypotrichosis and mutation in the DSG4 gene. She was born with light curly hair that easily broke and shed when touched or pulled. At age 1 year, the remaining original light curly hair turned straight and dark and no new hair appeared in the areas of shedding, leaving prominent hair roots and follicular hyperkeratotic papules. Some of her eyebrows and eyelashes also broke and shed. Teeth, nails, and sweating were normal. A biopsy of an area of sparse hair from the occiput revealed curled ingrown hair shafts within the hair follicle, due to their inability to penetrate the epidermis, with focal swelling inside the follicle. The authors noted that although beaded hairs were not visible to the naked eye, evidence of monilethrix was apparent in macroscopic images from skin confocal laser scanning microscopy, which revealed hairs of different diameters and lengths, with the elliptical nodes and nearly transparent constrictions being most prominent on short broken hairs. In addition, many dark hyperkeratotic papules were observed at the ostium of hair follicles, with accumulation of keratin within the follicles confirmed on confocal images. SEM examination of hair shafts revealed marked warping, curling, cracking, and detachment of the hair cuticle, and transmission electron microscopy (TEM) showed notable disruption of cell-cell adhesion in the outer root sheath. The authors stated that this was the first patient of Chinese origin diagnosed with localized hypotrichosis.

Zhou et al. (2022) reported 3 unrelated Chinese patients with monilethrix-like hypotrichosis and mutation in the DSG4 gene. All patients had sparse fragile hair involving the scalp, eyebrows, and eyelashes, with erythematous pruritic keratotic follicular papules since birth. Although hair beading was not seen under light microscopy, all 3 patients had monilethrix-like atypical beaded hairs and broken hair shaft fragments visualized using dermoscopy. Histopathology of affected scalp showed hyperkeratosis and acanthosis at the follicular orifice with plugging, and transections showed curled ingrown vellus-like hair shaft fragments. One of the patients (patient 1) also exhibited enamel hypoplasia.

Clinical Variability

Cohen-Barak et al. (2018) reported 2 unrelated Muslim Arab children who had localized congenital hypotrichosis with follicular keratotic papules and mutation in the DSG4 gene. Patient 1 was a 10-year-old girl who presented in infancy with hypotrichosis of the eyebrows and eyelashes. Examination showed hypotrichosis of the eyebrows that was more prominent in the lateral third, accompanied by follicular papules and focal atrophy, as well as hypotrichosis of the lower eyelids. She had dry skin, and widespread follicular keratotic papules were observed over the face, scalp, and extremities; biopsy of a keratotic papule revealed hair follicles with a widened infundibulum. Scalp hair appeared normal, with mild diminution in the frontal area, and her hair was not fragile or pluckable. The proband's deceased maternal grandmother was reported to have had a similar phenotype. Patient 2 was a 2.5-year-old boy who also exhibited hypotrichosis of the eyebrows and lower eyelashes, as well as generalized follicular keratotic papules over the face, scalp, trunk, and extremities. His scalp hair was dense. Microscopy of hair from both patients did not show any changes in the hair shaft. The authors suggested that the patients' phenotype represented DGS4-associated keratosis pilaris atrophicans (see KPA, 604093).

The transmission pattern of HYPT6 in the families reported by Kljuic et al. (2003) and Wajid et al. (2007) was consistent with autosomal recessive inheritance.

Kljuic et al. (2003) performed genomewide linkage analysis in 2 consanguineous Pakistani pedigrees with LAH. They obtained a maximum 2-point lod score of 4.63 for marker D18S866 (theta = 0.0), combining the lod score values from the 2 pedigrees. Multipoint analysis supported linkage to this region, with maximum lod scores exceeding 5.0 throughout the interval D18S1149 to D18S1135 on chromosome 18q12.

Using a candidate gene approach to localize the hypotrichosis locus segregating in 3 consanguineous Pakistani kindreds, Rafique et al. (2003) found linkage of the disorder to a 5.5-cM region on chromosome 18q21.1, obtaining a maximum 2-point lod score of 5.25 at marker D18S36 (theta = 0.0).

In 7 Iraqi patients with monilethrix-like hypotrichosis and 20 Iraqi controls, Zlotogorski et al. (2006) used microsatellite markers to analyze 9 candidate gene clusters and found homozygosity for the 219-bp allele of a marker on chromosome 18q in all of the patients and 3 controls. Haplotype analysis with 2 additional markers from the cluster on 18q revealed a homozygous haplotype that was found in all of the patients but in none of the controls (p less than 0.0001).

Kljuic et al. (2003) identified an identical homozygous 5-kb deletion within the DSG4 gene (607892.0001) in affected individuals from 2 Pakistani families with localized autosomal recessive hypotrichosis (LAH). Rafiq et al. (2004) identified the same deletion in the 3 Pakistani families in whom Rafique et al. (2003) had identified linkage to chromosome 18q21.1.

In 6 affected members of a large consanguineous Pakistani family with hypotrichosis, Wajid et al. (2007) identified homozygosity for a 1-bp deletion in the DSG4 gene (607892.0002).

In a Japanese girl with monilethrix-like congenital hypotrichosis, who was negative for mutation in the 3 keratin genes known to cause autosomal dominant monilethrix (158000), Shimomura et al. (2006) identified compound heterozygosity for mutations in the DSG4 gene (607892.0003-607892.0004). The authors suggested that LAH and monilethrix overlap and should not be regarded independently.

In a 2-year-old girl of Iraqi and Iranian Jewish descent, who had monilethrix-like congenital hypotrichosis and was negative for mutation in the 3 keratin genes known to cause autosomal dominant monilethrix, Schaffer et al. (2006) identified compound heterozygosity for mutations in the DSG4 gene (607892.0005-607892.0006). Her affected fraternal twin brothers were also compound heterozygotes for the mutations. Schaffer et al. (2006) stated that these cases expanded the LAH phenotype to include monilethrix-like hairs and cutaneous fragility of the scalp in the neonatal period.

In 7 Iraqi Jewish patients with monilethrix-like congenital hypotrichosis mapping to a gene cluster on chromosome 18q, Zlotogorski et al. (2006) sequenced the candidate gene DSG4 and identified homozygosity for a missense mutation (607892.0007). Subsequently, compound heterozygosity for 3 additional mutations were detected, including a splice site mutation and a 1-bp deletion in patients of Iranian descent (607892.0008 and 607892.0009, respectively) and a nonsense mutation in patients of Moroccan descent (607892.0010). Zlotogorski et al. (2006) suggested that the lack of classical hair shaft beading in previously reported LAH1 patients might be explained by the different mutations involved or by a different genetic background, but also noted that in some patients beading may be very scarce and may be overlooked unless dermatoscopic examination is performed to identify the distorted monilethric short hairs. Zlotogorski et al. (2006) concluded that despite the lack of microscopic hair shaft findings in LAH, there is considerable clinical overlap between LAH and patients with monilethrix-like congenital hypotrichosis.

In a 2-year-old Chinese girl with monilethrix-like congenital hypotrichosis, Wang et al. (2015) sequenced the DSG4 gene and identified homozygosity for a missense mutation (D323G; 607892.0009) that segregated with disease in the family and was not found in 100 unrelated controls or in public variant databases. The authors concluded that localized hypotrichosis and monilethrix should not be regarded as independent diseases but as part of a spectrum with variable expressivity.

In 2 apparently unrelated Muslim-Arab children with localized congenital hypotrichosis and follicular keratotic papules, Cohen-Barak et al. (2018) identified homozygosity for the same 4-bp deletion in the DSG4 gene (607892.0010). The deletion, which was verified by Sanger sequencing and segregated with the phenotype in both families, was not found in 107 ethnicity-matched DNA samples or in the ExAC or gnomAD databases.

In 3 unrelated Chinese patients with monilethrix-like hypotrichosis, Zhou et al. (2022) identified biallelic mutations in the DSG4 gene, including homozygosity for a large 48,644-bp deletion starting in intron 1 of DSG4 and extending to the downstream intergenic region between DSG4 and DSG3 (169615) (patient 3). Familial segregation was confirmed in patients 1 and 2, and none of the variants were found in 50 controls. The authors reviewed previously reported patients with DSG4-associated hypotrichosis, noting that monilethrix-like hair changes are best detected using dermoscopic examination of short thin hairs, and that these changes may not be observed in long thick terminal hair obtained by pulling, plucking, or cutting.

Kiener et al. (2022) studied 2 unrelated domestic shorthair cats with hair shaft dystrophy and mutations in the Dsg4 gene. Case 1 was a female that showed generalized hypotrichosis at 3 months of age, with symmetric hair loss affecting the convex pinnae and parts of the face, back, and legs, including the dorsal paws. The cat was mildly pruritic. The trichogram showed broken and split hair shafts, with severe bulbous swellings. Case 2 was a male that previously had been studied by Rostaher et al. (2021) and exhibited progressive alopecia of the back, the plantar and palmar surfaces of the limbs, the convex pinnae, and most of the face. All of the cat's littermates showed similar skin lesions. Macroscopic and microscopic evaluation revealed many short broken hair shafts, some with bulbous or lance-shaped ends. Histopathology showed that numerous hair shafts were dystrophic, with severe well-circumscribed thickening of the shafts starting above the melanogenic zone. There was loss of the ladder-like pattern of pigment distribution. The dystrophy was characterized by an irregular outer contour of the hair shaft, fragmentation within the cortex and cuticle, and dense eosinophilic cornified material surrounding the hair shaft. The authors noted that the phenotype resembled that of Dsg4-null mice. Genomic analysis in both cats revealed different 1-bp deletions in the Dsg4 gene, causing frameshifts predicted to result in premature termination codons, truncating 98% and 43% of the open reading frame, respectively. The mutations were confirmed by Sanger sequencing and were not found in 46 unaffected cats.

Kljuic et al. (2003) used the symbol LAH for this form of hereditary hypotrichosis.

Wali et al. (2007) noted clinical similarities among 3 genetically distinct forms of hypotrichosis with affected individuals having normal beard hair (in men) and sparse to absent eyebrows, eyelashes, and body hair; they suggested that the form mapped to chromosome 18 be designated LAH1, the form mapped to chromosome 3q27 be designated LAH2, and the form mapped to 13q14-q21 be designated LAH3.